Molecular and Cellular Biology, vol. 25(17), 2005, pp. 7812-7827
Department of Neurobiology and Anatomy
Drexel University College of Medicine
2900 W. Queen Lane, Room186
Sasaki, S., Mori, D., Toyo-oka, K., Chen, A., Garrett-Beal, L., Muramatsu, M., … Hirotsune, S. (2005). Complete Loss of Ndel1 Results in Neuronal Migration Defects and Early Embryonic Lethality. Molecular and Cellular Biology, 25(17), 7812–7827.
Sasaki, Shinji, D. Mori, K. Toyo-oka, Amy Chen, L. Garrett-Beal, M. Muramatsu, S. Miyagawa, et al. “Complete Loss of Ndel1 Results in Neuronal Migration Defects and Early Embryonic Lethality.” Molecular and Cellular Biology 25, no. 17 (2005): 7812–7827.
Sasaki, Shinji, et al. “Complete Loss of Ndel1 Results in Neuronal Migration Defects and Early Embryonic Lethality.” Molecular and Cellular Biology, vol. 25, no. 17, 2005, pp. 7812–27.
ABSTRACT Regulation of cytoplasmic dynein and microtubule dynamics is crucial for both mitotic cell division and neuronal migration. NDEL1 was identified as a protein interacting with LIS1, the protein product of a gene mutated in the lissencephaly. To elucidate NDEL1 function in vivo, we generated null and hypomorphic alleles of Ndel1 in mice by targeted gene disruption. Ndel1 −/− mice were embryonic lethal at the peri-implantation stage like null mutants of Lis1 and cytoplasmic dynein heavy chain. In addition, Ndel1 −/− blastocysts failed to grow in culture and exhibited a cell proliferation defect in inner cell mass. Although Ndel1 +/− mice displayed no obvious phenotypes, further reduction of NDEL1 by making null/hypomorph compound heterozygotes (Ndel1 cko/− ) resulted in histological defects consistent with mild neuronal migration defects. Double Lis1 cko/+ -Ndel1 +/− mice or Lis1 +/− -Ndel1 +/− mice displayed more severe neuronal migration defects than Lis1 cko/+ -Ndel1 +/ + mice or Lis1 +/− -Ndel1 +/+ mice, respectively. We demonstrated distinct abnormalities in microtubule organization and similar defects in the distribution of β-COP-positive vesicles (to assess dynein function) between Ndel1 or Lis1-null MEFs, as well as similar neuronal migration defects in Ndel1- or Lis1-null granule cells. Rescue of these defects in mouse embryonic fibroblasts and granule cells by overexpressing LIS1, NDEL1, or NDE1 suggest that NDEL1, LIS1, and NDE1 act in a common pathway to regulate dynein but each has distinct roles in the regulation of microtubule organization and neuronal migration.